Multiple sclerosis (MS) represents one of the most frequent causes of disability in early to middle adulthood. The cognitive impairment affecting approximately half of MS patients is a primary reason for disability in this disorder, and it exacts a tremendous socioeconomic and interpersonal toll on patients and their families. The PIs recently obtained exciting results in a small NCMRR funded pilot clinical trial to treat cognitive impairment in MS and seek a competitive renewal with this proposal. In the previous study, the acetylcholinesterase inhibitor donepezil enhanced the learning and memory of impaired MS patients on a standardized primary outcome as compared to placebo. Patients and clinician also noted significantly improved memory and cognition in the donepezil versus placebo group. Some patients on donepezil commented that they no longer became lost while driving, that they better remembered to pay their bills on time, or that they were able to return to full time work. Since prior efforts to rehabilitate cognitive impairment in MS have met with little success, confirming the efficacy of donepezil would lead to a new and improved standard of care for this population. Further study is critical since these positive results were obtained in a relatively small sample at a single site. The proposed investigation will provide a crucial test of these results across multiple centers in a definitive clinical trial. If donepezil again improves learning and memory, and effects are evident to patients, their significant others, and clinicians, it will alter practice guidelines for treating cognitive impairment in MS, and improve the quality of life of affected individuals. To this end, the PIs propose a multicenter, double blind, randomized, placebo controlled, parallel group clinical trial of donepezil in 144 cognitively impaired MS patients to demonstrate the efficacy of this intervention. Specific Aim 1: To determine the efficacy of donepezil in the treatment of cognitive impairment in MS patients. It is hypothesized that donepezil will enhance verbal memory and self-reported cognitive function. Specific Aim 2: To examine the relationship of treatment response to baseline subject characteristics, such as baseline neuropsychological performance, and MS subtype. [unreadable] [unreadable]